The myometrium plays a fundamental role in a variety of female reproductive events and has a significant impact on pregnancy outcome. The structural and functional abnormalities of myometrium can lead to reproductive disorders, such as implantation failure, preterm labor, and uterine rupture, some of which are severe causes of neonatal mortality and morbidity. Despite the long-recognized importance of myometrial function in pregnancy, key signaling pathways that control myometrial development and function are not well defined. Lack of this knowledge is partially due to the lack of an animal model with myometrial defects resulting from disruption of defined cell signaling pathways. This creates a significant barrier that prevents an effective therapeutic intervention for myometrial dysfunction. Our objective of this proposal is to define the role of transforming growth factor (TGF) signaling in myometrium, and identify the contribution of dysregulated TGF signaling to the development of uterine diseases. We hypothesize that TGF signaling is required for myometrial development and function, and dysregulated myometrial TGF signaling is linked to uterine diseases such as adenomyosis. We will test our hypothesis in two specific aims: 1) Identify the role of TGF signaling in myometrial contractility and pregnancy; and 2) Define the mechanistic contributions of dysregulated TGF signaling to the development of myometrial defects and uterine adenomyosis. To achieve these aims, we will use complementary approaches including a conditional knockout strategy and in vitro assays to test our working hypotheses. Successful completion of the proposed application will help to uncover the signaling pathways that control the structural and functional properties of the myometrium, and achieve a new paradigm for understanding the mechanisms underlying myometrial pathologies. These data could potentially guide the design of novel therapies for myometrial dysfunction and myometrium-associated diseases. PUBLIC HEALTH RELEVANCE: Our proposal is relevant to the mission of NICHD because TGF signaling pathway is critical in regulation of female reproduction. The myometrium plays a fundamental role in a variety of female reproductive events and has a significant impact on pregnancy outcome. Therefore, uncovering the role of TGF signaling pathway in myometrial development and function will potentially lead to the discovery of novel diagnostic and therapeutic strategies for myometrial dysfunction and uterine diseases.